What Is Gemcitabine (Gemzar)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA-Approved: Yes (First approval date: 15 May 1996)
• Brand Name and Manufacturer, Distribution in Turkey: The original brand is Gemzar (Eli Lilly). It is also available under generic names: Gemcitabin Koçak (Koçak Farma), Gemto (Onko & Koçsel), Gemcitabin Sandoz (Sandoz), Gemcitar (Nobel İlaç), and Gemsar (Saba İlaç).
• Active Ingredient: Gemcitabine
• Route of Administration: Intravenous (IV) infusion
• Class: Antimetabolite
• Category: Chemotherapy agent
• Manufacturer: Eli Lilly
• Approved Cancers: Pancreatic, non-small cell lung, breast, ovarian, and bladder cancers

What Is Gemcitabine?

Gemcitabine is a fluorine-modified deoxycytidine analog with cell cycle-specific antitumor activity, particularly in S phase. It stops cancer cell growth and causes their death.

How Does Gemcitabine Work?

• Cellular Uptake: Gemcitabine enters cells through nucleoside transporter proteins on the cell surface.
• Activation: Within the cell, deoxycytidine kinase activates it to the monophosphate form, followed by conversion to the diphosphate and triphosphate forms.
• Inhibition of DNA Synthesis: The active triphosphate form halts DNA synthesis. It is incorporated into the DNA chain and prevents elongation, stopping cell division.
• Disruption of DNA Repair: By disrupting DNA repair, it disables mechanisms that allow cancer cells to survive.
• Disruption of RNA Metabolism: It affects RNA synthesis, disrupting protein production and cell function.
• Suppression of Tumor Growth: Its effects on both DNA and RNA stop tumor cell growth and proliferation.
• Selective Toxicity: It particularly targets rapidly dividing cancer cells, causing less damage to healthy cells.

FDA (US Food and Drug Administration) Approval History

• 15 May 1996:  Pancreatic Cancer: Approved as monotherapy for locally advanced or metastatic pancreatic cancer.
• 1 December 1998:  Non-Small Cell Lung Cancer (NSCLC): Approved with cisplatin for inoperable, locally advanced, or metastatic NSCLC.
• 19 July 2004:  Metastatic Breast Cancer:  Approved with paclitaxel for metastatic breast cancer in patients resistant to anthracycline-based regimens or whose disease progressed after these treatments.
• 9 July 2006:  Ovarian Cancer: Approved with carboplatin for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer sensitive to platinum-based regimens.
• 22 November 2006:  Bladder Cancer: Approved with cisplatin for locally advanced or metastatic bladder cancer.
• 8 July 2010:  Ovarian Cancer (Additional Approval): Additional approval with carboplatin for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer sensitive to platinum-based regimens.
• 6 March 2024:  Urothelial Carcinoma (With Cisplatin and Nivolumab): Approved with cisplatin and nivolumab for first-line treatment of unresectable or metastatic urothelial carcinoma.

Licensing in Turkey

The conditions / therapeutic indications for which gemcitabine is licensed in Turkey are stated as follows:

Therapeutic indications:

• Bladder Cancer
  • Gemcitabine is indicated alone or with platinum-derived drugs for advanced (locally advanced or metastatic) bladder cancer.
• Non-small cell lung cancer
  • Gemcitabine is indicated with cisplatin for first-line treatment of locally advanced or metastatic non-small cell lung cancer. If cisplatin is contraindicated, it may be used alone or with cytostatic drugs.
• Breast cancer
  • Gemcitabine is indicated as part of combination therapy for locally advanced or metastatic breast cancer. Previous treatment should have included an anthracycline unless clinically contraindicated.
• Pancreatic cancer
  • Gemcitabine is indicated for patients in good general condition with locally advanced or metastatic pancreatic adenocarcinoma and adequate bone marrow reserve.
• Ovarian cancer
  • Gemcitabine is indicated for recurrent ovarian cancer resistant to platinum or taxanes.

Is Gemcitabine Reimbursed?

It is on the list of drugs for which no specific indication requirement applies when cancer is diagnosed. It is reimbursed by Turkey's SGK for all cancer diagnoses.

Price: Gemzar 200 mg 1 vial: 32.48 TL, Gemzar 1000 mg 1 vial: 159.53 TL

Resistance Mechanism

• Reduced Cellular Uptake Transporter Proteins: Reduced expression of transporter proteins responsible for gemcitabine uptake prevents drug entry into cells and reduces its effect.
• Increased Metabolic Enzymes Such as Cytidine Deaminase: Increased levels of enzymes such as cytidine deaminase in cancer cells rapidly convert gemcitabine to inactive metabolites, reducing its effect.
• Increased DNA Replication Fork Stability: Cancer cells try to prevent gemcitabine's effect by increasing the stability of the DNA replication fork it targets.
• Competitive Mechanisms in Nucleotide Metabolism: Cancer cells increase natural nucleotide concentrations to create a competitive environment and prevent gemcitabine from reaching its target.
• Activation of DNA Repair Mechanisms: Cancer cells may activate alternative DNA repair mechanisms to reduce gemcitabine's cell-killing effect.

Absorption

Gemcitabine is administered only intravenously (IV). Absorption depends on infusion duration.

Distribution

Gemcitabine's distribution depends on infusion duration:

• Short Infusions (≤70 minutes): Gemcitabine does not distribute widely in the body.
• Long Infusions (>70 minutes): Gemcitabine distributes slowly and extensively into body tissues.
• Does Not Cross the Blood-Brain Barrier: Its effect on the central nervous system is limited.
• Plasma Protein Binding: Gemcitabine's plasma protein binding is negligible.

Metabolism

Gemcitabine is extensively metabolized to  difluorouridine (dFdU) ; approximately 90% of the drug is excreted in urine in this form. Deamination occurs in the liver, plasma, and peripheral tissues. Cytidine deaminase is the key enzyme in drug catabolism. 

The terminal elimination half-life depends on infusion duration. With short infusions (<70 minutes), it ranges from 30-90 minutes, while with long infusions (>70 minutes), it extends to 4-10 hours. Plasma clearance depends on age and sex; it is approximately 30% lower in women and older people.

Dosing Schedule

• Pancreatic Cancer:
  • Dose: 1,000 mg/m² by intravenous (IV) infusion over 30 minutes.
  • Regimen: Once weekly for the first 7 weeks, followed by one week off. Subsequently, weekly doses for 3 weeks are followed by 1 week off.
• Bladder Cancer:
  • Use Alone: 1,250 mg/m² by IV infusion over 30 minutes on days 1, 8, and 15 of each 28-day cycle.
  • Combination Therapy (With Cisplatin): 1,000 mg/m² by IV infusion over 30 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin is given at 70 mg/m² on day 1 or day 2.
• Ovarian Cancer:
  • Use Alone: 800-1,250 mg/m² by IV infusion over 30 minutes on days 1, 8, and 15 of each 28-day cycle.
  • Combination Therapy (With Carboplatin): 1,000 mg/m² by IV infusion over 30 minutes on days 1 and 8 of each 21-day cycle. Carboplatin follows gemcitabine on day 1, targeting an AUC of 4.0 mg/ml/min.
• Breast Cancer:
  • Combination Therapy (With Paclitaxel): 1,250 mg/m² by IV infusion over 30 minutes on days 1 and 8 of each 21-day cycle. On day 1, it is administered after a 3-hour paclitaxel infusion (175 mg/m²).
• Non-Small Cell Lung Cancer (NSCLC):
  • Use Alone: 1,000 mg/m² by IV infusion over 30 minutes, once weekly for 3 weeks, followed by one week off.
  • Combination Therapy (With Cisplatin):
    • 3-Week Regimen: 1,250 mg/m² by IV infusion over 30 minutes on days 1 and 8 of each 21-day cycle.
    • 4-Week Regimen: 1,000 mg/m² by IV infusion over 30 minutes on days 1, 8, and 15 of each 28-day cycle.

Drug Interactions

• Cisplatin: Gemcitabine enhances cisplatin's cytotoxic effect. In combination, the formation of platinum-DNA adducts increases, causing more damage to cancer cells.
• Radiotherapy: Gemcitabine has a strong radiosensitizing effect. Combined with radiotherapy, it increases cancer cells' sensitivity to radiation and enhances treatment efficacy.

Precautions

• Complete Blood Count Monitoring: Complete blood counts should be obtained regularly during treatment. Dose reduction or treatment interruption should be considered for hematological toxicity.
• Hepatic and Renal Impairment: Use cautiously in patients with abnormal liver and/or kidney function. Regular monitoring is recommended because of increased toxicity risk.
• Women and Older Patients: Gemcitabine clearance may decrease in women and older patients, potentially prolonging its effects.
• Pregnancy and Breastfeeding: Pregnancy category D. Avoid use during pregnancy; use in breastfeeding mothers is completely contraindicated.

Adverse Effects

Reported adverse effects, from most to least common, are:

1. Myelosuppression: A dose-dependent adverse effect whose most common manifestations are neutropenia, thrombocytopenia, and anemia. The nadir usually occurs on days 10-14, with recovery by day 21.
2. Nausea and Vomiting: Usually mild to moderate, occurring in 70% of patients. Diarrhea and/or mucositis has been reported in 15-20%.
3. Flu-Like Syndrome: Presents with fever, fatigue, chills, headache, and muscle pain. Observed in 20% of patients. Fever without infection may develop within the first 6-12 hours after treatment and is generally mild.
4. Hepatotoxicity: Associated with increased serum transaminases and bilirubin.
5. Pulmonary Toxicity: Pulmonary toxicity may occur as mild shortness of breath and drug-induced pneumonia. Acute respiratory distress syndrome (ARDS) has rarely been reported.
6. Infusion Reaction: May involve flushing, facial swelling, headache, shortness of breath, and/or hypotension. It generally depends on infusion rate and resolves when the infusion is slowed or stopped.
7. Renal Toxicity: Mild proteinuria and hematuria may occur. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) have rarely been reported.
8. Skin Reactions: Maculopapular rash and itching generally affect the trunk and extremities. Radiation recall dermatitis may occur. Alopecia is rare.